NCT02987010

Phase 2 Study of IDH305 in Low Grade Gliomas

A Phase 2 Study of the IDH1 Inhibitor, IDH305, for the Treatment of IDH1 Mutated Low Grade Glioma Patients Who Have Measurable 2HG by MR Spectroscopy

• Status: Withdrawn
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 0 (actual)
• Sponsor: University of Texas Southwestern Medical Center · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Cohort A - neoadjuvant administration of IDH305 at 550 mg BID for 6 weeks followed by surgical resection at 6 weeks. If there is no evidence of progressive disease at 6 weeks (clinical, radiographic or histopathologic exam), the patient will continue on IDH305 at 550 mg BID post-operatively for a maximum of 11 additional 28 day cycles. Subsequent assessment of disease will occur every 2 months starting in Cycle 2. Cohort B - patients who have inoperable tumors but measurable 2HG pre-treatment will be treated with IDH305 at 550 mg BID x 6 weeks. If there is adequate sustained knockdown of 2HG on MRS and disease is stable or improved, then the patient will continue on treatment for a maximum of 11 additional 28 day cycles.

Detailed description

IDH1 mutations are thought to be among the earliest mutations occurring during transformation of glial cells into gliomas and dependence on the IDH-2HG pathway for survival and growth may be most relevant during the indolent phase of low grade tumor growth. However, the preclinical workup of IDH inhibitors was technically unable to assess low grade gliomas because the cells do not grow in vitro and so cannot be cultured, and the cells have such a low proliferation rate that they do not grow in mouse in vivo models. Despite this, Dr. Maher and colleagues have studied low grade metabolism in low grade gliomas in vivo, in patients undergoing surgical resection and infused with 13C-glucose or 13C-acetate. 13C-labeled tumor can be studied by 13C-nuclear magnetic resonance (NMR) ex vivo. 13C-NMR data from IDH-mutated low grade gliomas demonstrate that these tumors are highly metabolically active, capable of oxidizing both glucose and acetate while these substrates also contribute carbon to actively making 2HG (manuscript in preparation). These data strongly suggest that the low grade tumors may be dependent on the IDH pathway for maintaining the altered metabolic state of the cell and altered epigenome necessary for tumor growth. Treating low grade gliomas during the period of indolent growth poses a challenge in terms of evaluating a molecular targeted therapy for response and survival. Standard MRI assessment for low grade gliomas based on T2/FLAIR signal can be difficult to quantitate and reflects additional non-specific changes in the tumor microenvironment including edema and reactive gliosis. This is exacerbated by the natural history of these tumors for which there may be no change in tumor size over years. Added to this is the uncertainty that a drug was able to penetrate the blood brain barrier, enter the tumor and inhibit the target. To date, there is no non-invasive way to determine target inhibition, leaving the patients on a drug that may not inhibit the target and the investigator unsure if data being obtained reflects true activity. The current clinical trial addresses these challenges through a neoadjuvant clinical trial that combines non-invasive evaluation of 2HG by MRS to assess target inhibition within 1 week of study entry and direct tumor tissue analysis after 6 weeks on study in the surgical cohort. The comprehensive planned tissue analysis is designed to assess the impact of IDH305 on metabolic pathways, the epigenome and transcriptome, in addition to standard assessment of cellular proliferation and cell kill. A second cohort of patients, the non-surgical cohort, will include patients with a presumptive diagnosis of IDH-mutated glioma based on elevated 2HG on screening 2HG MRS but without a surgical resection planned because of perceived high risk of the procedure. It is anticipated that \~ 93% of these patients will have an IDH1 mutation and thus treatment with the IDH1 selective inhibitor will knockdown 2HG. For patients with an IDH2 mutation (\~7-8%), we anticipate that there will be no change in 2HG. These patients will come off study, sparing them any potential toxicity without potential benefit.

Conditions

• Glioma

Interventions

Type	Name	Description
DRUG	IDH305	Isocitrate Dehydrogenase 1 inhibitor

Timeline

• Start date: 2017-01-01
• Primary completion: 2019-01-01
• Completion: 2019-01-01
• First posted: 2016-12-08
• Last updated: 2017-10-11